Abstract
ATP-driven efflux transporters at the blood-brain barrier both protect against neurotoxicants and limit drug delivery to the brain. In other barrier and excretory tissues, efflux transporter expression is regulated by certain ligand-activated nuclear receptors. Here we identified constitutive androstane receptor (CAR) as a positive regulator of P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and breast cancer resistance protein (BCRP) expression in rat and mouse brain capillaries. Exposing rat brain capillaries to the CAR activator, phenobarbital (PB), increased the transport activity and protein expression (Western blots) of P-glycoprotein, Mrp2, and BCRP. Induction of transport was abolished by the protein phosphatase 2A inhibitor, OA. Similar effects on transporter activity and expression were found when mouse brain capillaries were exposed to the mouse-specific CAR ligand, 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP). In brain capillaries from CAR-null mice, TCPOBOP did not increase transporter activity. Finally, treating mice with 0.33 mg/kg TCPOBOP or rats with 80 mg/kg PB increased P-glycoprotein-, Mrp2-, and BCRP-mediated transport and protein expression in brain capillaries assayed ex vivo. Thus, CAR activation selectively tightens the blood-brain barrier by increasing transport activity and protein expression of three xenobiotic efflux pumps.
Footnotes
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.063685.
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ABBREVIATIONS:
- ABC
- ATP-binding cassette
- CNS
- central nervous system
- CAR
- constitutive androstane receptor
- PXR
- pregnane X receptor
- PCN
- pregnenolone 16α-carbonitrile
- TCPOBOP
- 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene
- NBD-CSA
- [N-°(4-nitrobenzofurazan-7-yl)-d-Lys8]-cyclosporine A
- Mrp
- multidrug resistance-associated protein
- BCRP
- breast cancer resistance protein
- OA
- okadaic acid
- PB
- phenobarbital
- LTC4
- leukotriene C4
- FTC
- fumitremorgin C
- PP2A
- protein phosphatase 2A
- BSA
- bovine serum albumin
- PBS
- phosphate-buffered saline
- PSC833
- valspodar
- MK571
- 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
- Ko143
- (3S, 6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester.
- Received January 20, 2010.
- Accepted June 14, 2010.
- U.S. Government work not protected by U.S. copyright
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